Estrogen receptors

In the tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist.

A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects.

Selective receptor modulators

Some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists.

Inverse agonists

The ligand binding domain of the estrogen receptor is complexed with either the agonist diethylstilbestrol or antagonist 4-hydroxytamoxifen. When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LDB (H12) is positioned such that a coactivator protein can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so called NR box containing the LXXLL amino acid sequence motif. Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a side chain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

Stuctural basis for the mechanism of nuclear receptor agonist and antagonist action.

Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators, Selective Estrogen Receptor Modulators and Selective Progesterone Receptor Modulators. The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism.

Estrogen receptors are a group of proteins found inside cells, are activated by the estrogen (17β-estradiol). Two classes of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 (GPER), which is a G protein-coupled receptor.

Дата добавления: 2014-01-14